Pharmaceutical multiparticulates

ABSTRACT

A process for the manufacture of particles comprises mechanically working a mixture of a drug and a hydrophobic and/or hydrophilic fusible carrier in a high speed mixture so as to form agglomerates, breaking the agglomerates to give controlled release particles and optionally continuing the mechanical working with the optional addition of a low percentage of the carrier or diluent.

This is a divisional of application Ser. No. 08/343,630, filed Nov. 22,1994, now abandoned.

BACKGROUND OF THE INVENTION

The present invention relates generally to a method of manufacturingpharmaceutical dosage forms, for human or veterinary use, preferablysustained release particles, such particles having diameters rangingfrom 0.1 to 3.0 mm. Such particles may contain analgesics, such asmorphine, or other active ingredients. The present invention alsorelates to dosage forms obtained by processing of the aforesaidparticles, such as tablets, suppositories or pessaries.

Patent Application PCT/SE93/00225 published under No. WO 93/18753describes a process for the preparation of sustained release pelletswhich comprises pelletizing a mixture containing the drug in finelydivided form and a binder; the process is characterized in that:

(a) the binder is in particle form consisting of one or morewater-insoluble or water-soluble, wax-like binder substance(s) with amelting point above 40° C. and

(b) the pelletization step is performed by mechanically working themixture, in a so-called high-shear mixer, under the input of asufficient amount of energy for the binder to melt and pelletization totake place. Patent Application PCT/SE92/06679 describes a similarprocess.

Processes of this kind are sometimes referred to as "melt-pelletization"processes. We have found that operating according to these processesusing commercial manufacturing equipment with a standard stainless steelinterior, which is also the method described in Schaefer et al. (DrugDevelopment and Industrial Pharmacy, 16(8), 1249-1277 (1990) and Taggartet al. (International Journal of Pharmaceutics 19 (1984) 139-148),results in yields of pellets in the preferred size range of only about30 to 60% compared with the theoretical. Use of a wider particle sizerange to improve the yield results in an erratic in vitro release rateand irreproducible performance.

There is, therefore, a need for a commercial process for producingsatisfactory controlled release particles which has a much higher yield.One object of the invention is, therefore, to provide a process whichhas an improved yield and preferably produces a product withreproducible controlled release characteristics.

The present invention thus includes in one aspect a process for themanufacture of particles, preferably sustained release particles, whichcomprises

(a) mechanically working in a high-speed mixer, a mixture of aparticulate drug and a particulate, hydrophobic and/or hydrophilicfusible carrier or diluent having a melting point from 35° to 150° C.and optionally a release control component comprising a water solublefusible material or a particulate, soluble or insoluble organic orinorganic material, at a speed and energy input which allows the carrieror diluent to melt or soften, whereby it forms agglomerates;

(b) breaking down the larger agglomerates to give controlled releaseparticles; optionally

(c) continuing mechanically working optionally with a further additionof low percentage of the carrier or diluent; and

(d) optionally repeating step (c) and possibly (b) one or more, e.g. upto five, times.

This process is capable of giving a high yield (over 80%) of particlesin a desired size range, with a desired in vitro release rate and,uniformity of release rate.

The resulting particles may be sieved to eliminate any oversized orundersized material then formed into the desired dosage units by forexample, encapsulation into hard gelatin capsules containing therequired dose of the active substance or by tabletting, filling intosachets or molding into suppositories, pessaries or forming into othersuitable dosage forms.

The drug may be water soluble or water insoluble. Water soluble drugswill usually be used in amounts giving for example a loading of up toabout 90% w/w in the resulting particles; water insoluble drugs may beused in higher amounts eg. up to 99% w/w of the resulting particles.Examples of water soluble drugs which can be used in the method of theinvention are morphine, hydromorphone, diltiazem, diamorphine andtramadol and pharmaceutically acceptable salts thereof; examples ofwater insoluble drugs which can be used in the process of the inventionare naproxen, ibuprofen, indomethacin and nifedipine.

Among the active ingredients which can be used in the process of theinvention are the following;

ANALGESICS

Dihydrocodeine, Hydromorphone, Morphine, Diamorphine, Fentanyl,Alfentanil, Sufentanyl, Pentazocine, Buprenorphine, Nefopam,Dextropropoxyphene, Flupirtine, Tramadol, Oxycodone, Metamizol,Propyphenazone, Phenazone, Nifenazone, Paracetamol, Phenylbutazone,Oxyphenbutazone, Mofebutazone, Acetyl salicylic acid, Diflunisal,Flurbiprofen, Ibuprofen, Diclofenac, Ketoprofen, Indomethacin, Naproxen,Meptazinol, Methadone, Pethidine, Hydrocodone, Meloxicam, Fenbufen,Mefenamic acid, Piroxicam, Tenoxicam, Azapropazone, Codeine.

ANTIALLERGICS

Pheniramine, Dimethindene, Terfenadine, Astemizole, Tritoqualine,Loratadine, Doxylamine, Mequitazine, Dexchlorpheniramine, Triprolidine,Oxatomide.

ANTIHYPERTENSIVE

Clonidine, Moxonidine, Methyldopa, Doxazosin, Prazosin, Urapidil,Terazosin, Minoxidil, Dihydralazin, Deserpidine, Acebutalol, Alprenolol,Atenolol, Metoprolol, Bupranolol, Penbutolol, Propranolol, Esmolol,Bisoprolol, Ciliprolol, Sotalol, Metipranolol, Nadolol, Oxprenolol,Nifedipine, Nicardipine, Verapamil, Diltiazem, Felodipine, Nimodipine,Flunarizine, Quinapril, Lisinopril, Captopril, Ramipril, Fosinopril,Cilazapril, Enalapril.

ANTIBIOTICS

Democlocycline, Doxycycline, Lymecycline, Minocycline, Oxytetracycline,Tetracycline, Sulfametopyrazine, Ofloxacin, Ciproflaxacin, Aerosoxacin,Amoxycillin, Ampicillin, Becampicillin, Piperacillin, Pivampicillin,Cloxacillin, Penicillin V, Flucloxacillin, Erythromycin, Metronidazole,Clindamycin, Trimethoprim, Neomycin, Cefaclor, Cefadroxil, Cefixime,Cefpodoxime, Cefuroxine, Cephalexin, Cefradine.

BRONCHODILATOR/ANTI-ASTHMATIC

Pirbuterol, Orciprenaline, Terbutaline, Fenoterol, Clenbuterol,Salbutamol, Procaterol, Theophylline, Cholintheophyllinate,Theophylline-ethylenediamine, Ketofen.

ANTIARRHYTHMICS

Viquidil, Procainamide, Mexiletine, Tocainide, Propafenone, Ipratropium.

CENTRALLY ACTING SUBSTANCES

Amantadine, Levodopa, Biperiden, Benzotropine, Bromocriptine,Procyclidine, Moclobemide, Tranylcypromine, Tranylcypromide,Clomipramine, Maprotiline, Doxepin, Opipramol, Amitriptyline,Desipramine, Imipramine, Fluroxamin, Fluoxetin, Paroxetine, Trazodone,Viloxazine, Fluphenazine, Perphenazine, Promethazine, Thioridazine,Triflupromazine, Prothipendyl, Thiothixene, Chlorprothixene,Haloperidol, Pipamperone, Pimozide, Sulpiride, Fenethylline,Methylphenildate, Trifluoperazine, Thioridazine, Oxazepam, Lorazepam,Bromoazepam, Alprazolam, Diazepam, Clobazam, Clonazepam, Buspirone,Piracetam.

CYTOSTATICS AND METASTASIS INHIBITORS

Melfalan, Cyclophosphamide, Trofosfamide, Chlorambucil, Lomustine,Busulfan, Prednimustine, Fluorouracil, Methotrexate, Mercaptopurine,Thioguanin, Hydroxycarbamide, Altretamine, Procarbazine.

ANTI-MIGRAINE

Lisuride, Methysergide, Dihydroergotamine, Ergotamine, Pizotifen.

GASTROINTESTINAL

Cimetidine, Famotidine, Ranitidine, Roxatidine, Pirenzipine, Omeprazole,Misoprostol, Proglumide, Cisapride, Bromopride, Metoclopramide.

ORAL ANTIDIABETICS

Tolbutamide, Glibenclamide, Glipizide, Gliquidone, Gliboruride,Tolazamide, Acarbose and the pharmaceutically active salts or esters ofthe above and combinations of two or more of the above or salts oresters thereof.

The hydrolysis of drugs constitutes the most frequent, and perhapstherefore the most important, route of drug decomposition. Analysis of acollection of stability data in Connors KA, Amidon GL, Stella VJ,Chemical stability of pharmaceuticals: A handbook for pharmacists, 2nded. New York: John Wiley & Sons, 1986, a standard text, shows that over70% of the drugs studied undergo hydrolytic degradation reactions. Ofthese, 61.4% can be classed as reactions of carboxylic acid derivatives(esters, amides, thiol esters, lactams, imides), 20% of carbonylderivatives (imines, oximes) 14.3% of nucleophilic displacements, and4.3% of phosphoric acid derivatives. Cephalosporins, penicillins andbarbituates are particularly susceptible drug classes.

The process of the invention may advantageously be used for preparingdosage forms containing active substances as mentioned above which areunstable in the presence of water, e.g. diamorphine. Thus stableformulations of such drugs having normal or controlled releasecharacteristics can be obtained in accordance with the invention.

In a preferred method according to the invention morphine sulphate, orother water soluble drug, e.g. tramadol, is used in an amount whichresults in particles containing e.g. between <1% and 90%, especiallybetween about 45% and about 75% w/w active ingredient for a high doseproduct and e.g. <1 and 45% for a low dose product.

In the method of the invention preferably all the drug is added in step(a) together with a major portion of the hydrophobic or hydrophilicfusible carrier or diluent used. Preferably the amount of fusiblecarrier or diluent added in step (a) is between e.g. 10% and <99% w/w ofthe total amount of ingredients added in the entire manufacturingoperation.

The fusible carrier or diluent may be added stepwise during mechanicalworking, in step a) or step c).

In step (c) the amount of additional fusible carrier or diluent added ispreferably between 5% and 75% w/w of the total amount of ingredientsadded.

Stage (a) of the process may be carried out in conventional high speedmixers with a standard stainless steel interior, e.g. a Collette Vactron75 or equivalent mixer. The mixture is processed until a bed temperatureabove 40° C. is achieved and the resulting mixture acquires a cohesivegranular texture, with particle sizes ranging from about 1-3 mm to finepowder in the case of non-aggregated original material. Such material,in the case of the embodiments described below, has the appearance ofagglomerates which upon cooling below 40° C. have structural integrityand resistance to crushing between the fingers. At this stage theagglomerates are of an irregular size, shape and appearance.

The agglomerates are preferably allowed to cool. The temperature towhich it cools is not critical and a temperature in the range roomtemperature to 41° C. may be conveniently used.

The agglomerates are broken down by any suitable means, which willcomminute oversize agglomerates and produce a mixture of powder andsmall particles preferably with a diameter under 2 mm. It is currentlypreferred to carry out the classification using a Jackson Crockattgranulator using a suitable sized mesh, or a Comil with an appropriatesized screen. We have found that if too small a mesh size is used in theaforementioned apparatus the agglomerates melting under the action ofthe beater or impeller will clog the mesh and prevent further throughputof mixture, thus reducing yield.

The classified material is preferably returned to the high speed mixerand processing continued. It is believed that this leads to cementationof the finer particles into particles of uniform size range.

In one preferred form of the process of the invention processing of theclassified materials is continued, until the hydrophobic and/orhydrophilic fusible carrier or diluent materials used begin tosoften/melt and additional hydrophobic and/or hydrophilic fusiblecarrier or diluent material is then added; most preferably theadditional hydrophobic and/or hydrophilic fusible carrier or diluentmaterial is added after any fines generated in stage (b) have been takenup by the larger sized particles. Mixing is continued until the mixturehas been transformed into particles of the desired predetermined sizerange.

In order to ensure uniform energy input into the ingredients in the highspeed mixer it is preferred to supply at least part of the energy bymeans of microwave energy.

Energy may also be delivered through other means such as by a heatingjacket or via the mixer impeller and chopper blades.

After the particles have been formed they are sieved to remove anyoversized or undersized material and then cooled or allowed to cool.

The resulting particles may be used to prepare dosage units, e.g.,tablets or capsules in manners known per se.

In this process of the invention the temperature of the mixing bowlthroughout the mechanical working is chosen so as to avoid excessiveadhesion, suitably to minimize adhesion of the material to the walls ofthe bowl. To minimize adhesion we have generally found that thetemperature should be neither too high nor too low with respect to themelting temperature of the material and it can be readily optimized toavoid the problems mentioned above. For example in the processesdescribed below in the Examples a bowl temperature of approximately50°-60° C. has been found to be satisfactory and avoids adhesion to thebowl. It is not possible to generalize as to the appropriate temperaturefor any particular mixture to be processed. However, in practice, it isa matter of simple experimentation and observation to establish asuitable temperature and processing time for a particular mixture underconsideration.

The process of the invention described above is capable, in a preferredform, of providing particles which function as sustained release dosageforms. In particular, as described in co-pending European PatentApplication No. 94303128.6 filed on 29th Apr. 1994, an orallyadministrable sustained release dosage unit form containing morphine, ora pharmaceutically acceptable salt thereof, as active ingredient whichformulation has a peak plasma level of morphine from 1 to 6 hours afteradministration.

We have found that by suitable selection of the materials used informing the particles and in the tabletting and the proportions in whichthey are used, enables a significant degree of control in the ultimatedissolution and release rates of the active ingredients from thecompressed tablets.

Suitable substances for use as hydrophobic carrier or diluent materialsare natural or synthetic waxes or oils, for example hydrogenatedvegetable oil, hydrogenated castor oil, Beeswax, Carnauba wax,microcrystalline wax and glycerol monostearate, and suitably havemelting points of from 35° to 150° C., preferably 45° to 90° C.

Suitable substances for use as hydrophilic carrier or diluent materialsare natural or synthetic waxes or oils, for example polyethylene glycols(PEGs) having molecular weights of 1000 to 20,000 e.g. 1,000 to 6,000 or10,000 suitably having melting points of from 35° to 150° C., preferably45° to 90° C.

The optionally added release control component when a water soluble,fusible material may be a PEG of appropriate molecular weight; suitableparticulate inorganic and organic materials are, for example dicalciumphosphate, calcium sulphate, talc, colloidal anhydrous silica, andlactose, poloxamers, microcrystalline cellulose, starch,hydroxypropylcellulose, and hydroxypropylmethylcellulose.

We have also found that particles produced by the melt pelletizationprocesses described in application PCT/SE93/00225 and the processdescribed herein are particularly useful for processing into the form oftablets.

To produce tablets in accordance with the invention, particles producedas described above may be mixed or blended with the desiredexcipient(s), if any, using conventional procedures e.g. using a Y-Coneor bin-blender and the resulting mixture compressed according toconventional tabletting procedure using a suitably sized tablettingtooling. Tablets can be produced using conventional tabletting machines,and in the embodiments described below were produced on standards singlepunch F3 Manesty machine or Kilian RLE15 rotary tablet machine.

Generally speaking we find that even with highly water soluble activeagents such as morphine or tramadol tablets formed by compressionaccording to standard methods give very low in-vitro release rates ofthe active ingredient e.g. corresponding to release over a period ofgreater than 24 hours, say more than 36. We have found that the in vitrorelease profile can be adjusted in a number of ways. For instance in thecase of water soluble drugs a higher loading of the drug will beassociated with increased release rates; the use of larger proportionsof the water soluble fusible material in the particles or surface activeagent in the tabletting formulation will also be associated with ahigher release rate of the active ingredient: Thus, by controlling therelative amounts of these ingredients it is possible to adjust therelease profile of the active ingredient, whether this be water solubleor water insoluble.

In Drug Development and Industrial Pharmacy, 20(7), 1179-1197 (1994) byL J Thomsen et al, which was published after the priority date of thisapplication, a process similar to that described in PCT/SE93/00225 isdiscussed in detail. In the results and discussion on page 1186 it isstates that glyceryl monostearate was the only substance which showedpronounced potential as a meltable binder, and then only with mixerslined with polytetrafluoroethylene. By contrast the process of thepresent invention has been found to work satisfactorily with otherbinders and using conventional mixers with stainless steel linings.

In Pharmaceutical Technology Europe October 1994 pp 19-24 L J Thomsendescribes the same process as mentioned in the above article. In thepassage bridging pages 20 and 21 it is stated higher drug loads withlarger drug crystals did not pelletize and that his results suggestmanufacturers using melt pelletization should avoid starting materialscontaining amounts of crystals larger than 60 μm and that electrostaticcharging of mass and adhesion to the walls of the mixer bowl made itimpossible to make acceptable quality pellets with a binder of puremicrocrystalline wax so that substantial amounts of glycerolmonostearate was essential. In the process of the invention describedherein drug crystal size has not been found to be a critical parameter;in the Examples described below the morphine sulphate typically has aparticles size distribution with 50% of particles larger than 24 to 50μm and 10% larger than 100-140 μm.

In order that the invention may be well understood the followingexamples are given by way of illustration only.

EXAMPLES Examples 1 TO 4

Particles, having the formulations given in Table I below, were preparedby the steps of:

i) Placing the ingredients (a) to (c) (total batch weight 20 kg) in thebowl of a 75 liter capacity Collette Vactron Mixer (or equivalent)equipped with variable speed mixing and granulating blades;

ii) Mixing the ingredients at about 150-350 rpm while applying heatuntil the contents of the bowl are agglomerated.

iii) Classifying the agglomerated material by passage through a Comiland/or Jackson Crockatt to obtain controlled release particles.

iv) Adding the classified material to the heated bowl of a 75 literCollette Vactron, allowing the particles to heat up under mixing, thenadding ingredient (d), and continuing the mechanical working untiluniform particles of the desired predetermined size range are formed inyields of greater than 80%.

v) Discharging the particles from the mixer and sieving them to separateout the particles collected between 0.5 and 2 mm aperture sieves andthen allowing them to cool.

                  TABLE I    ______________________________________    EXAMPLE          1         2      3    ______________________________________    a)    Morphine Sulphate                         55.0      52.19                                        53.48          (wt %) B.P.    b)    Hydrogenated Vegetable                         34.95     33.17                                        33.98          Oil USNF (wt %);    c)    Polyethylene Glycol                         0.05      0.047                                        0.049          6000 USNF (wt %)    d)    Hydrogenated Vegetable                         10.0      14.60                                        12.49          Oil USNF (wt %)    YIELD %          90.5      83.4   90.1    ______________________________________

The in-vitro release rates of Examples 1, 2 and 3 were assessed bymodified Ph. Eur. Basket method at 100 rpm in 900 ml aqueous buffer (pH6.5) containing 0.05% w/v polysorbate 80 at 37° C. (corresponding to thePh. Eur. Basket method but using a basket with a finer mesh, with thesame open area and with a slightly concave top). For, each of theproducts, six samples of the particles, each sample containing a totalof 60 mg of morphine sulphate were tested. The results set out in TableII below give the mean values for each of the six samples tested.

                  TABLE II    ______________________________________    PRODUCT OF EXAMPLES    HOURS AFTER   1           2     3    START OF TEST % MORPHINE RELEASED    ______________________________________    2             21          15    20    4             33          25    36    6             43          35    49    8             52          43    59    12            62          57    72    18            74          71    82    24            82          81    86    30            83          85    89    ______________________________________

The procedure of Example 3 was repeated but the operation varied byadding the classified particles to a cold bowl of the Collette Vactron,followed by adding ingredient (d) and mixing, heating by jacket heatingand microwave being applied during mixing. The in-vitro release rate,obtained using the same procedure as for Examples 1 to 3, is given inTable IIa and demonstrates that although the composition of the productsin Examples 3 and 4 are the same the different processing results inmodified release rates.

                  TABLE IIa    ______________________________________    PRODUCT OF EXAMPLE 4    HOURS AFTER     % MORPHINE    START OF TEST   RELEASED    ______________________________________    2               15    4               24    6               30    8               36    12              46    18              57    24              65    30              71    ______________________________________

Particles produced according to Examples 1 to 4 were each blended withpurified talc and magnesium stearate and used to fill hard gelatincapsules such that each capsule contains 60 mg of morphine sulphate. Thecapsules produced were used in open, randomized crossoverpharmacokinetic studies. As part of these studies patients receivedafter overnight fasting either one capsule according to the invention orone MST CONTINUS® tablet 30 mg (a twice a day preparation). Fluid intakewas unrestricted from 4 hours after dosing. A low-fat lunch was providedfour hours after dosing, a dinner at 10 hours post dose and a snack at13.5 hours post-dose. No other food was allowed until a 24 hourpost-dose blood sample had been withdrawn. Blood samples were taken atthe following times 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 9, 12, 18, 24, 36,48 and 72 hours post-dose.

The pharmacokinetic studies using these capsules gave peak plasma levelsof from 3.2 to 29.2 ng/ml of morphine at median times between 2 and 6hours following administration and blood sampling according to the aboveprotocol.

The capsules containing particles produced according to Examples 2 and 4in particular gave a mean C_(max) of 11.9 ng/ml at median t_(max) 4hours and mean C_(max) of 9.2 ng/ml at median t_(max) 2.5 hoursrespectively (these values represent the mean of the individual C_(max)and t_(max) values). In contrast the C_(max) and t_(max) for thepatients who received MST CONTINUS® tablets were 10.6-11.4 ng/ml and2.0-2.5 hours respectively. It was found, however, that the plasmaconcentrations of morphine in the blood of patients given capsulesaccording to the invention at 24 hours were greater than theconcentrations at 12 hours in those patients given MST CONTINUS tablets.

Example 5

Particles were produced analogously to Examples 1 to 4 but having thefollowing ingredients

    ______________________________________                      wt %    ______________________________________    Morphine sulphate   55.0    Hydrogenated vegetable oil                        44.7    Polyethylene glycol 6000                        0.3    ______________________________________

Samples of the particles were then blended with magnesium stearate andpurified talc in two lots (1 and 2) using a Y-Cone or bin-blendermachine. The blended mixtures were then each compressed on a 7.1 mmdiameter normal concave tooling on a single punch F3 Manesty tablettingmachine. The ingredients per dosage unit amounted to the following:

                  TABLE III    ______________________________________                      Mg/Tablet    Tablet Ingredient   1       2    ______________________________________    Morphine Sulphate   60.00   60.00    Hydrogenated Vegetable Oil                        48.77   48.77    Polyethylene Glycol 0.33    0.33    Sub Total           109.1   109.1    Magnesium Stearate  1.42    2.0    Purified Talc       2.18    3.0    ______________________________________

The dissolution of the samples of non-compressed particles (each samplecontaining 60 mg of morphine sulphate) was assessed by the modified Ph.Eur. Basket method described above. For the dissolution of the tabletsthe Ph. Eur. Basket was replaced by the Ph. Eur. Paddle Method. Theresults are shown in Table IV below:

                  TABLE IV    ______________________________________    HOURS AFTER               % MORPHINE SULPHATE RELEASED    START OF TEST               PARTICLES   TABLET 1  TABLET 2    ______________________________________    1          27          13        11    2          43          20        17    4          63          29        26    8          82          42        37    12         88          50        44    16         91          57        NR    24         93          65        NR    30         94          70        NR    36         95          74        NR    ______________________________________     NR = Not recorded

The above results show that the tabletting procedure results in aconsiderable reduction in the release rate of the active ingredient.

Example 6

The procedure of Example 5 was repeated but with the followingvariations.

The particles were made with the following ingredients.

    ______________________________________                           wt %    ______________________________________    Morphine Sulphate        55 .0    Hydrogenated Vegetable Oil                             44.4    Polyethylene Glycol 6000 0.6    ______________________________________

Two lots of tablets (3 and 4) were produced from the particles using a7.1 mm diameter concave tooling. The ingredients per dosage unit were asfollows:

                  TABLE V    ______________________________________                      Mg/Tablet    Tablet Ingredient   3       4    ______________________________________    Morphine Sulphate   60.0    60.0    Hydrogenated Vegetable Oil                        48.44   48.44    Polyethylene Glycol 6000                        0.655   0.655    Sub Total           109.1   109.1    Poloxamer 188       --      5.0    Magnesium Stearate  2.0     2.0    Purified Talc       3.0     3.0    ______________________________________

The dissolution of the tablets and samples of non-compressed particles(each sample containing 60 mg of morphine sulphate) were assessed by themethods described above.

The results are shown in Table VII below:

                  TABLE VI    ______________________________________    HOURS AFTER               % MORPHINE SULPHATE RELEASED    START OF TEST               PARTICLES   TABLET 3  TABLET 4    ______________________________________    1          56          16        19    2          75          24        28    4          90          34        38    8          95          46        52    12         97          54        60    16         NR          NR        67    24         NR          NR        77    ______________________________________     NR = Not recorded

These results demonstrate again a dramatic reduction in the release rateof the morphine sulphate resulting from compression tabletting of theparticles; comparison of the release rates for Tablets 3 and 4 also showthat the release rate can be adjusted by use of a surface active agent(in this case Poloxamer 188®) as a tabletting excipient, the releaserate for tablet 4 which contains the surface active agent being greaterthan that for tablet 3 without the surface active agent.

Example 7

A procedure analogous to Example 5 was carried out using tramadolhydrochloride as active ingredient in place of morphine sulphate. Theparticles were made with the following ingredients:

    ______________________________________                      wt %    ______________________________________    Tramadol Hydrochloride                        50    Hydrogenated Vegetable Oil                        50    ______________________________________

Three lots of tablets (5, 6 and 7) were produced from particles usingrespectively (a) 14 mm×6 mm, (b) 16 mm×7 mm and (c) 18.6 mm×7.5 mmcapsule shaped tooling. The ingredients per dosage unit were as follows:

                  TABLE VII    ______________________________________                   Mg/Tablet    Tablet Ingredient                     5         6       7    ______________________________________    Tramadol HCl     200       300     400    Hydrogenated Vegetable Oil                     200       300     400    Sub Total        400       600     800    Purified Talc    12.63     18.95   25.26    Magnesium Stearate                     8.42      12.63   16.84    ______________________________________

The tablets were assessed by dissolution in 0.1N HCl Ph. Eur. Paddle at100 rpm. For the non-compressed particles the Ph. Eur. Paddle wasreplaced by the modified Ph. Eur. Basket, each sample of particlescontaining 400 mg of tramadol hydrochloride. The results are shown inTable VIII below:

                  TABLE VIII    ______________________________________    HOURS    AFTER    START   % TRAMADOL HCl RELEASED    OF                TABLET     TABLET TABLET    TEST    PARTICLES 5          6      7    ______________________________________    1       54        16         15     15    2       68        23         20     21    3       76        28         25     25    4       82        32         28     28    6       89        40         35     35    8       93        46         41     40    10      96        50         45     45    12      98        55         49     49    16      100       63         57     56    20      NR        70         63     NR    ______________________________________     NR = Not recorded

These results confirm the effectiveness of the tabletting in reducingthe release rate of tramadol, a highly water soluble drug.

Example 8

The procedure of Example 7 was repeated but with a higher loading oftramadol hydrochloride in the particles. Thus particles were made withthe following Ingredients;

    ______________________________________                      wt %    ______________________________________    Tramadol Hydrochloride                        75    Hydrogenated Vegetable Oil                        25    ______________________________________

Three lots of tablets (8, 9 and 10) were produced from the particlesusing respectively tooling (a), (b) and (c) described in Example 7. Theingredients per unit dosage were as follows:

                  TABLE IX    ______________________________________                   Mg/Tablet    Tablet Ingredient                     8         9       10    ______________________________________    Tramadol HCl     200       300     400    Hydrogenated Vegetable Oil                     66.7      100     133    Sub Total        266.7     400     533    Purified Talc    7.63      11.44   15.25    Magnesium Stearate                     5.16      7.63    10.17    ______________________________________

The tablets and samples of non-compressed particles (each samplecontaining 400 mg of tramadol hydrochloride) were assessed by themethods described in Example 7. The results are shown in Table X below:

                  TABLE X    ______________________________________    HOURS    AFTER    START    % TRAMADOL HCl RELEASED    OF TEST  PARTICLES TABLET 8  TABLET 9                                         TABLET 10    ______________________________________    1        77        43        40      42    2        92        64        55      56    3        98        75        65      66    4        100       83        72      73    6        102       94        83      84    8        102       100       91      91    10       102       NR        96      97    ______________________________________     NR = Not recorded

These results show that by increasing the loading of the highly watersoluble tramadol hydrochloride (75% w/w in this example compared with50% w/w in Example 7) a significantly faster release rate of the activeingredient can be achieved.

Example 9

0.35 kg particulate diamorphine hydrochloride and the same weight ofparticulate hydrogenated vegetable oil (Lubritab) were placed in thebowl of a Collette Gral 10 or equivalent mixer, preheated to 60° C.Mixing was carried out at the following speeds for the Collette Gral10--mixer 350 rpm; chopper 1500 rpm, until the contents of the bowl areslightly agglomerated. The agglomerates are then allowed to cool toapproximately 40° C., are removed from the bowl and are milled in aComill to obtain controlled release seeds. The seeds are then placed inthe mixer bowl and processing carried out until multiparticulates of adesired size are obtained. The contents of the bowl are then dischargedand sieved to collect the 0.5-2.0 mm sieve fraction.

The procedure described in the preceding paragraph was repeated but thecollected sieve fraction is blended in a conventional blender with 0.006kg talc for 5 minutes; 0.004 kg magnesium stearate is then added and theblending continued for 3 minutes. The blend is then discharged andcompressed using a 4 mm×8 mm capsule shaped tooling on a F3 tabletmachine. The resulting tablet had a hardness of 1.7 kp, a thickness of2.8-3.0 mm and a friability of <1.0% and the following conditions:.

                  TABLE XI    ______________________________________    CONSTITUENT        MG/TABLET  % W/W    ______________________________________    Diamorphine Hydrochloride                       40.0       47.6    Hydrogenated Vegetable Oil                       40.0       47.6    Talc               2.40       2.86    Magnesium Stearate 1.6        1.91    TOTAL              84    ______________________________________

The dissolution rates of the resulting multiparticulates and tablets,measured respectively by the Ph. Eur. Basket or Paddle method at 100 rpmin either phosphate or acetate buffer, were as follows:

                  TABLE XII    ______________________________________    % DIAMORPHINE HCL RELEASED                            Tablets  Tablets            Multiparticulates                            Paddle/  Paddle/    TIME    Basket/Phosphate                            Phosphate                                     Acetate    (HRS)   Buffer          Buffer   Buffer    ______________________________________    1       30              --       24    2       44              35       35    3       54              41       43    4       62              47       49    6       70              57       59    8       78              64       67    12      87              75       78    16      92              84       86    ______________________________________

The examples provided above are not meant to be exclusive. Many othervariations of the present invention would be obvious to those skilled inthe art, and are contemplated to be within the scope of the appendedclaims.

What is claimed is:
 1. Pharmaceutical particles of an opioid analgesic,which provide a time to peak plasma level of said opioid in about 2 toabout 6 hours after administration, produced by a process comprising thesteps of:(a) mechanically working in a high-speed mixer, a mixture ofsaid opioid analgesic in particulate form and a particulate, hydrophobicand/or hydrophilic fusible carrier or diluent having a melting pointfrom 35° to 150° C. at a speed and energy input which allows the carrieror diluent to melt or soften whereby it forms agglomerates; (b) breakingdown the agglomerates to give controlled release particles; andoptionally (c) continuing mechanically working optionally with theaddition of a low percentage of the carrier or diluent. 2.Pharmaceutical particles according to claim 1 wherein said particleshave a size range of about 0.5 to about 2 mm.
 3. Pharmaceuticalparticles according to claim 1, wherein said hydrophobic carrier is atleast 25 percent by weight of the total amount of ingredients added. 4.Pharmaceutical particles according to claim 1, wherein said hydrophobiccarrier is at least about 45 percent by weight of the total amount ofingredients added.
 5. Pharmaceutical particles according to claim 1,wherein during the mechanical working, step (c), heat is suppliedthereto by microwave radiation.
 6. Pharmaceutical particles according toclaim 5, wherein only part of the heating is supplied by microwaveradiation.
 7. Pharmaceutical particles according to claim 1, whereinsaid opioid analgesic is morphine, tramadol, hydromorphone, oxycodone,diamorphine or a pharmaceutically acceptable salt thereof. 8.Pharmaceutical particles according to claim 1, wherein said particlesprovide a plasma concentration of said opioid analgesic effective toprovide an analgesic effect for about 24 hours after administration. 9.Pharmaceutical particles according to claim 1, wherein said opioidanalgesic comprises from about 1% to about 90% of said particles. 10.Pharmaceutical particles according to claim 9, wherein the hydrophobicfusible carrier comprises from about 10% to about 99% of said particles.11. Pharmaceutical particles according to claim 10, wherein said opioidanalgesic is morphine sulphate and said hydrophobic fusible carrier ishydrogenated vegetable oil, said morphine and said hydrogenatedvegetable oil being present in a ratio of about 1.1:1 to about 1.25:1.12. The pharmaceutical particles according to claim 10, wherein saidhydrophilic agent is PEG which comprises from about 0.047% to about 0.6%of said mixture.
 13. Pharmaceutical particles according to claim 10,wherein said opioid analgesic is tramadol hydrochloride and saidhydrophobic fusible carrier is hydrogenated vegetable oil, said tramadoland said hydrogenated vegetable oil being present in a ratio of about3:1.
 14. Pharmaceutical particles according to claim 10, wherein saidopioid analgesic is diamorphine hydrochloride and said hydrophobicfusible carrier is hydrogenated vegetable oil, said diamorphine and saidhydrogenated vegetable oil being present in a ratio of about 1:1. 15.Pharmaceutical particles according to claim 1, wherein said releasecontrol component is selected from the group consisting of polyethyleneglycol, dicalcium phosphate, calcium sulfate, talc, colloidal anhydroussilica, lactose, poloxamers, microcrystalline cellulose, starch,hydroxypropyl-cellulose and hydroxypropylmethylcellulose. 16.Pharmaceutical particles according to claim 1, wherein the particlesfurther comprise a release control component selected from the groupconsisting of a water soluble fusible material, a particulate solubleorganic material, a particulate soluble inorganic material, aparticulate insoluble organic material, a particulate insolubleinorganic material, and mixtures thereof.
 17. Pharmaceutical particlesaccording to claim 1, wherein said particles are compressed into atablet.
 18. Pharmaceutical particles according to claim 1, wherein saidparticles are contained in a capsule.
 19. Pharmaceutical particlesaccording to claim 1, wherein said agglomerates further comprise arelease control component comprising a water-soluble fusible material ora particulate, soluble or insoluble organic or inorganic material. 20.Pharmaceutical particles according to claim 1, wherein said processfurther comprises the step of repeating steps (c) one or more times. 21.Pharmaceutical particles according to claim 1, wherein said high-speedmixer is a high-shear mixer.
 22. Pharmaceutical particles according toclaim 1, wherein said high-speed mixer is a Collette Vactron Mixer orequivalent.
 23. Pharmaceutical particles according to claim 1, whereinsaid process further comprises the step of repeating steps (b) one ormore times.